Ethers of 3-alkylamino-4-methyl-7-hydroxy-coumarin



United States Patent tice 3,3 l LS Patented Mar. 28, 1967 3,311,635 ETHERS F 3-ALKYLAll/11N0-4-IVIEIHYL-7- AlItYllRXY-C(NUIVIARIN' tVV Heinrich Ritter, Dornigheim, Kreis Hanau, and Rudi Beyerie and Rolf-Eberhard Nitz, Frankfurt am Main-'- This application is a division of parent application Ser.

No. 212,657, tiled .luly 26, `1962, now U.S. YPatentY The administration of coronary vasodilators is to bring about an enhanced blood flow in the coronary vessels. The conventional coronary vasodilators, however, in- Volve the disadvantage of exercising merely a non-specific vasodilator action on'the coronary vessels because they simultaneously cause a dilatation of other large blood vessel areas, which is symptomatic of a considerable decrease in blood pressure. This hypotension does not allow the use of the known coronary vasodilators in hypotonic patients and in those having Van acute myocardial infarction. In such cases the known agents may even evoke a paradoxical effect onV the coronary Vessels, namely a coronary blood ow decreasing effect (see Scheler and Bretschneider, Verhandlungen der deutschen Gesellschaft fr Kreislaufforschung, vol. 26, page 254 (1960). Moreover, the known coronary vasodilator have vonly a relatively short-term action.

Consequently, the objective of our interest has been directed to the development of such coronary vasodilators as specically dilate the coronary vessels only and, thus, do not exhibit a hypotensive action and which especially possess a long-term activity.

Now, we have found that the desired properties inhere in the derivatives of the 7-hydroXy-coumarine of the general formula wherein R1 is a substituent of the group consisting of a hydrogen atom, an alkyl, alkenyl, aryl, aralkyl, heteroalkyl, aminoalkyland a carbalkoxyalkyl-radical, R2 is a substituent of the group consisting of an alkyland aryl residue, R3 is a substituent of the group consisting of an alkenyl, carbalkoxyalkyh, carboXyalkyl-, carbarnidoalkyl radical and, if R1 is an amionalkyl radical, furthermore, an alkyl radical and R4 is a substituent of the group consisting of a hydrogen atom and the residue -O'R3.

The new 7-hydroXy-coumarin derivatives are obtained in the known methods by allowing 7hydroxycoumarins of the general formula wherein R4' is a hydrogen atom or a hydroxyl group, to react with halogen compounds of the formula RsHal, in the presence of an acid-bindingagent, or by condensing with cyclization substituted hydroxy-cinnamic acids of the gener-al formula ,Y

| Re R1 R30 -OH or their functional derivatives or by condensing oxybenzenes of the general formula R30 -OH or, if R3 has the meaning of a carbamido-alkyl radical. by aminating 7-hydroXy-coumarin derivatives of the general formula alkyl- C O O-alkylene- O \O /=O with ammonia or primary or secondary amines.

The 7-hydroxycoumarins being required, inter alia, as starting products may be obtained according to known methods, by condensing in the presence of an acid condensation agent -keto-acid esters of the general formula being correspondingly substituted with hydroxybenzenes of the general formula HO OH Following the pharmacological tests in laboratories, which are described hereinafter the most active derivatives of the 7-hydroXy-coumarins had been subjected to clinical experimentation, the results of which will also be stated hereinafter.

The pharmacological investigation of the substances according to our present invention with respect to their coronary vasodilator action was carried out in dogs according to the method disclosed by Eckenhotf, Hafkenscording to the method disclosed by Eckenhol, Hafkenschiel and Landmeser (Am. J Physiol. 148, 582 (1947)). The test preparations were applied intravenously to the animals narcotized. The coronary blood flow Was measured by means of an automatic bubblediow-meter and the blood pressure was measured in the femoral artery by means of an Anderson glass-capsule manometer. During the test period the animals were given artiicial respiration. On these test conditions the dilatation of the coronary artery being caused by the test substance, gives rise to a more rapid bubble ow, whereas a constriction of the coronary vessels becomes evident from a retardation of the bubble iiow, which is recorded by a kymograph. In all these tests there was used papaverine as a comparative standard substance.

FIGURES 1 and 2 illustrate graphically the results obtained when using different amounts of papaverine in comparison to 3--diethylaminoethyl-4-methyl-coumarin- 7-ethyl oxyacetate chlorhydrate.

Within each gure:

Curve I represents the action of 0.4 mg./ kg. papaverine,

Curve II represents the action of 0.8 mgJkg. papaverme.

Curve III represents the action of 0.8 ing/kg. 3-,5- diethylaminoethyl-4-methyl-coumarin-7-ethyl oxyacetate chlorhydrate,

Curve IV represents the action of 1.265 mg./kg. 3-13- diethylaminoethyl-4-methyl-coumarin-7-ethyl oxyacetate chlorhydrate,

Curve V represents the action of 2 mg./kg. 3 diethylaminoethyl-l-methyl-coumarin-7-ethyl oxyacetate chlorhydrate.

FIGURE 1 indicates the influence of the substance upon the coronary flow and FIGURE 2 the influence upon the blood pressure. The data forming basis of the diagram represent the mean value of the results of measurement ascertained in tests on 8 animals each. The administration of doses higher than 0.8 mg./kg.'papaverine is irnpossible because otherwise a too sharp decrease in blood pressure occurs. The ligures show the clear superiority of the hydroxy-coumarin derivative under our invention over the standard substance papaverine Which,.on the one hand lies in the degree of the influence upon the coronary ow and on the other hand, in the duration of this influence (see FIGURE l) and, furthermore, they show the difference in the change of blood pressure (see FIG- URE 2).

On the same test conditions some further substances of our invention had pharmacologically been tested and the mean values of the test results obtained are indicated in the following table.

For clinical investigation there has been used especially the 3-diethylaminoethy1-4-methylcouniarin-7ethyl oxyacetate chlorhydrate. In various clinics the preparation was administered both in the form of drages and in the form of solutions for intravenous and intramuscular injection in the case of most diversified clinical appearances. The drages were administered in a dosage of 15-50 milligrams three times daily and the intravenous solution was given in a dosage of 10-20 milligrams once daily. In none of the cases, side-eiects of the substance had been observed. The following diagnoses had been made in the patients singled out for these tests: hypercholesterinemia,

coronary sclerosis, myocardial infarction, stenocarda, cardiosclerosis, coronary insuiciency and angina pectoris gravis. In practically all of the cases under examination a signicant improvement in the state of health of the patients was observed, which led to a complete redress of their pains and complaints.

In the preparation of drages and tablets containing as active ingredient the 7hydroxycoumarin derivatives of our invention, these substances may be admixed with solid tabletting adjuvants, such as starch, lactose, talc and the like. Any of the tabletting materials used in pharmaceu- LD50 Dosage, Maximum Duration of Change in Substance gJkg. nig/kg., increase in action in blood mouse, i.v. the coronary minutes pressure,

Lv. ow, percent percent Papaverine 0. 033 0. 8 24 8 -20 --dicthylaminoethyl-4-mothylconmarin-7- ethyl oxyacetate chlorhydrate 0. 034 0.8 22 60 +2 1. 265 35 60 |2 2.0 67 75 -4 3-5-pyrrolidinoethyl-i-methyl-cournarin-Y- ethyl oxyacetate chlorhydrate 0. 04 1.0 53 26 i0 --plperidinocthyl-4-methyl-cournarin-7 ethyl oxyacetate chlorhydrate O. 016 0.2 26 19 +2. 2 0. 4 37 28 0. 5 1.0 74 5.) i() {lp-morpholinoethyl 4mcthylcoumarin-7- ethyl oxyacctatc chlorhydrate 0.11 1. 0 21 16 i() B-Bpiperidinoethyl-l-metl1yl-7-allyl0xyeoumarin chlorhydrate 0. 048 1. O 94 30 +11. 3 S-B-diethylaminoethyl--l-phenyl cour11arin7 ethyl oxyocctatc chlorhydrate 0.02 1. 0 S8 40 1 -15 3[l.3bis(diethylamino)-isopropyl]4methyl coumarin7ethyloxyacetatc chlorhydrate 0. 05S 0. 8 43 65 3 diethylamnoethyl4rnethyl-cournarin7 oxyacetie acid aminoetliylamide 2.0 130 40 l Until 10 minutes after the injection, later :1n-0%.

Furthermore, comparative tests had been made on the same conditions as described before, however, with intracoronary administration of the following substances and papaverine in equal dosages.

-l-:having the same action as papaverine and -i--i-:having an action intenser and longer than papaverine tical practice may be employed. For the preparation of the injection solutions there are particularly suited the derivatives of the 7-hydroxy-coumarins being basically substituted since they are water-soluble in the form of their salts. Injection solutions of water-insoluble products may of course be prepared in the conventional manner by concurrently using Well-known suspending agents, emulsiers and/ or solubilizers.

The following examples are given for the purpose of characterizing the substances of the present invention. All temperatures given are in degrees centigrade.

Example 1 e Example 4 grams 3-phenyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of resorcin with a-phenyl-acetoacetic acid ethyl ester as indicated in I Chem. Soc. 109,

18 grams 3-butyl-4-methyl-7-hydroxy-coumarin (prepared by condensation of a-butylacetic acid ethyl ester with resorcin accorr ing to the method specified in Org. Synth., vol. 2l, page Z3), are suspended in 200 ccm. methylethyl ketone. 12 grams anhydrous potassium carbonate are added and the mixture is stirred for 1 hour at 70. Then 0.5 gram potassium iodide is introduced into the reaction mixture and 16 grams bromoacetic acid ethyl ester are allowed to drop in. The mixture is heated until boiling and stirred for 8 hours at the boil. Then the reaction mixture is filtered off With suction in the heat and worked up as indicated in Example 1. The raw product may be recrystallized from ethyl acetate for iurther purication. The 3-butyl-4-methyl-coumarin7ethyl oxyacetate thus obtained forms white needles having a melting point of 78.

Yield: 20 grams=83.5% of the theory.

Example 3 17.6 grams 4-methyl-7-hydroxy-coumarin (prepared by the method indicated in Org. Synth., vol. 21, page 23), are dissolved in 180 ccm. methylethyl ketone and, whilst adding 16 grams anhydrous potassium carbonate, they are allowed to react with 18.5 grams bromoacetic acid ethyl ester according to Example 1. Thus, 4-rnethyl-coumarin- 7-ethyl-oxyacetate having a melting point of 98-100 are obtained.

Yield: 19 grams=72.5% ofthe theory.

143 grams 4 pheny1.7 hydr0xy couman (prepared ac 110 and J. Chem. Soc. 127, 1983)., are suspended 1n 200 cording to the method specified in Org. Synth., vol. 21, CCmmethylethyl ketone and admlXed-W1'fh 20 grams an page 23, by condensation of benzoylacetic acid ethyl ester hydrous potassium carbonate. The mixture is stirred for with resorcin in concentrated sulfuric acid) are dissolved one hour at 70 and then 15 grams chloroacetic acid in 150 ccm. methylehtyl ketone and admixed with 10 10 tert. butyl ester are allowed to drop in. Subsequently, grams anhydrous potassium carbonate. This mixture is it is heated until boiling and stirred for another 9 hours SfTed for One hour at 70 and hel1 13 grams blOmO- at the boil. Now the reaction mixture is filtered oi with acetic aCd ethyl eSeT al'd 0 gram P0ta SSUm iodide are suction in the heat and the ltrate is concentrated in the added- It, 1S heated until bolhlg andmrd for 8 hotfs vacuum. The residue is dissolved in methylene chloride, at tlm lmll rhe reagun nxtur? 1S ltered (i Wlttlh l5 the solution is washed for several times with diluted glutlotdyn; anThte estdreteislsdsrr mlht sodium hydroxide solution and, subsequently, the methyl- .y ene chloride solution is concentrated in the vacuum to ene chloride, Washed several times with diluted sodium dr nass The remanin raw roduct rec talked hydroxide solution and the solution of methylene chloride f y Vb' g p 1S rys l is evaporated to dryness. The raw product may be re- 20 mn? enzme 1 crystallized from ethyl `acetate for further purification. Yleld' 20 grams 3'Pheny1'4jmethy 'coumannq'terg White needles having a melting point of 137-138 are butyl oxyacetate hal/mg a meltmg Point 0f 113415 obtained. (=69% of the theory).

Yield: i4 grams 4-pheny1-coumarin-7-erhyi oxyaceiate In an analogous manner, there may be prepared the (=71.8% of the theory). following 7-oxy-coumarin derivatives:

Starting materials Final product Melting Yield,

point, percent 3-phenyl+methyl7hy Chlonliaetic acid-iso- 3-phenyli-methrl-goumarin- 13S-140 70 d. x Y r. isopropy oxyace a e. -rehlylc-plhrlililrll-Lhylrlilrozcseic acid-tert. S-ethyl-l-phenyl-coumarin-L 122-123 64 droxy-cournarin. butyl ester. tert. butyl oxyacetate.

D0 Chlorpacititic acid-iso- .3-ethy14iphenyl-c%n inarm7 124-125 77 es er. ISODIOpy OXYECS a e. 3-benzyl-4-methyl-7-hyglirilirioacetie acid-ethyl 3-benzyl4methyl-coumarin-7 117-120 66 droxy-coumarin. ester. ethyl oxyacetate Example 2 Example 5 12 grams 3-ally1-4-methyl-7-hydroxy-coumarin are dissolved in ccm. methylethyl ketone and admixed with 12 grams anhydrous potassium carbonate. This mixture is stirred for 1 hour at 70 and then 11 grams bromoacetic acid ethyl ester are allowed to drop in. Then the mixture is stirred under reflux for another 9 hours. According to the recipe indicated in Example 1, 3-allyl-4- methyl-coumarin-7-ethyl oxyacetate having a melting point of 42-44 is obtained in a good yield.

Example 6 18.7 grains 3--diethylaminoethyl-4-methyl-7-hydroxycoumarin chlorhydrate are dissolved in 200 ccm. methylethyl ketone and 18 grains anhydrous potassium carbonate are added. The mixture is stirred for 1 hour at 70 and then y12 grams bromoacetic acid ethyl ester are a1- lov/ed to drop in. The reaction mixture is stirred under reiiux for 9 hours and then it is filtered ot With suction in the heat. The ltrate is concentrated in the vacuum to dryness and the resultant residue is dissolved in ether. The etheric solution is Washed with diluted caustic soda solution for several times and, subsequently, dried with Glaubers salt. By introduction of hydrochloric acid gas into the etheric solution the reaction product is precipitated in the form of chlorhydrate.

Yield: 15 grams 3--diethylaminoethyl-4-methyl-coumarin-7-ethyl oxyacetate chlorhydrate having a melting point of 154-156 (=63% of the theory).

According to the process described in this example there may be prepared in an analogous manner the following compounds of the general formula tion from Water, are colorless crystals having a melting point of 11S-119.

R3 O O Melting point R; R2 Rs oi the chlorhydrates,

-diethylaminoethyl `Hethy1 Etl1yl 22o-222 Do A11 l 198-201 D 288-290 -piperidinoethyL 220-222 -dietliylaminoethy 153-160 B-piperidinoethyL S-269 B-morpholinoethyL Qdi-:205 -pyrrolidinoethyl 182-183 y-dimethylaminopropyl ISO-182 l ,EK-bis (diethylamino)xsopropyl 176 The 3--diethylaminoethyl-4-methyl-coumarin-7 ethyl oxyacetate chlorhydrate described in this example can be saponiied to the free acid in a known method by dissolving 4 grams of the chlorhydrate in 40 ccm. water and heating this solution for 4 hours under reux. When subsequently concentrating the aqueous solution in the vacuum to dryness, a white crystalline residue is obtained which represents the 3--diethylaminoethyl-4-methy1-coumarin 7- oxyacetic acid chlorhydrate having a melting point of 70 75. The yield of the saponication is quantitative.

When using concentrated ammonia instead of ethylene diamine, there is obtained in an analogous manner the 3- -diethylaminoethyl-4-methyl-coumarin-7 oxyacetic acid amide in the form of colorless crystals having a melting point of 186-187".

When using in this example instead of ethylene diamine, one of the following amines, the corresponding amides of the 3--diethylaminoethyl-4-methyl-cumarin-7 oxyacetic acid are obtained:

Example 7 14 grams 3carbethoxymethyl-4methyl5,7djhydroxycoumarin (prepared by condensation of phloroglucine with acetylsuccinic acid diethyl ester according to the method indicated in Chemical Abstracts, vol. 37, 1430 2 (1943)), are suspended in 200 ccm. methylethyl ketone and 20 grams anhydrous potassium carbonate are added. This mixture is stirred for 1 hour at 70 and then 20 grams bromoacetic acid ethyl ester are allowed to drop in.

Then the mixture is heated until boiling and stirred for 9 hours at the boil. The reaction mixture is ltered oi with suction in the heat and the filtrate is concentrated in the vacuum to dryness. The residue is dissolved in methylene chloride and washed for several times with diluted caustic soda lye. After drying, the methylene chloride layer is concentrated in the vacuum to dryness and the yresidual raw product is puried by recrystallization from a mixture of ethyl acetate/benzine (1:1).

Yield: 13 grams 3carbethoxymethyl-l-methyl coumarin-5.7-di-(ethyl oxyacetate) having a melting point of 11G-112 (=57.5% of the theory).

Example 8 10 grams 3--diethylaminoethyl4methylcoumarin7 ethyl oxyacetate chlorhydrate are stirred together with 75 grams ethylene diamine for about 15 hours at 20-25. The resultant colorless precipitate is iiltered off with suction, washed with water and dried. Thus, 8 grams 3-- diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid aminoethylamide are obtained which, after recrystalliza- Example 9 18.7 grams 3--diethylaminoethyl-4methyl-7-hydroxy coumarin-chlorhydrate are suspended in 280 ccm. methylethyl ketone and, after the addition of 20 grams anhydrous potassium carbonate, the mixture is stirred for 4 hours at 70. Subsequently, a solution consisting of 9 grams N,N dimethyl-chloroacetamide in 25 ccm. methylethyl ketone is allowed to drop into the reaction mixture and is stirred for 8 hours at 70.

After cooling, the solution is ltered off with suction and the filtrate is concentrated in the vacuum to dryness; the residue is dissolved in ethyl acetate and washed for several times with diluted sodium hydroxide solution. The ethyl acetate layer is eliminated and dried. Hydrochloric acid gas is introduced into this solution for precipitating the chlorhydrate of the nal product. Thus, 3--diethylaminoethyl-4-methyl-coumarin-7-oxyacetic acid dimethylamide chlorhydrate is obtained having a melting point of 203-206.

Yield: 14 grams=59% of the theory.

In an analogous manner, there is obtained the 3--diethylaminoethyl-4-mcthyl-coumarin-7 oxyacetic acid dibutylamide chlorhydrate having a melting point lof l29 by allowing 3--diethylaminoethyl-4-methyl-7 hydroxy-coumarin-chlorhydrate to react with N,Ndibutyl chloroacetamide.

It will be understood Vthat this invention is susceptible to further modication and, accordingly, it is desired to comprehend such modifications within this invention as may fall within the scope of the appended claims.

9 10 We claim: 3. 3--diethylaminoethy1-4-methy1-7-butoxy coumarin 1. 3--diethylaminoethy1-4-methy1-7-ethoxy coumarin having the formula having the formula CH3 5 CrHr-N C2H5 H9C40 \O -O 4. 3--piperidinoethyl-4-methy1-7-ally1oxy coumarn 10 having the formula having the formula References Cited by the Examiner UNITED STATES PATENTS fllH CH 20 2,779,762 1/1957 Robertson et a1. 26o-294.3 2 3,141,893 7/1964 Pfister 26o-294.3 C2H4-N \C2H WALTER A. MODANCE, Primary Examiner. CHFCH-CHQ-O- -O o 25 AVROM D. SPEVACK, Assistant Examiner. 

4. 3-BPIPERIDINOETHYL-4-METHYL-7-ALLYLOXY - COUMARIN HAVING THE FORMULA 